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US6867333B2 - Epothilone synthesis building blocks iii and iv: asymmetrically substituted acyloins and acyloin derivatives, methods for their production and methods for the production of epothilones b, d and epothilone derivatives - Google Patents

Epothilone synthesis building blocks iii and iv: asymmetrically substituted acyloins and acyloin derivatives, methods for their production and methods for the production of epothilones b, d and epothilone derivatives Download PDF

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US6867333B2
US6867333B2 US10/414,510 US41451003A US6867333B2 US 6867333 B2 US6867333 B2 US 6867333B2 US 41451003 A US41451003 A US 41451003A US 6867333 B2 US6867333 B2 US 6867333B2
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mmol
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methyl
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dimethyl
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US20040082651A1 (en
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Ludger A. Wessjohann
Gunther Scheid
Uwe Bornscheuer
Erik Henke
Wouter Kuit
Romano Orru
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R and D Biopharmaceuticals GmbH
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Morphochem AG fuer Kombinatorische Chemie
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Definitions

  • the invention relates to acyloins, their derivatives, methods for their production and their use for the production of epothilones and their derivatives.
  • the invention relates to the building blocks for epothilone synthesis, methods for their production and the use of synthetic building blocks for the production of epothilones and their derivatives.
  • Acyloins or ⁇ -hydroxyketones (and -aldehydes) are important functional units in many biologically active substances. In addition, they are important synthetic intermediates and their small bifunctional unit is important as a site for double coupling with other synthetic building blocks, e.g. in heterocyclic chemistry.
  • acyloins in particular those in which the hydroxy group is esterified or otherwise protected or derivatized.
  • Acyloins with an unprotected hydroxy group are also designated as free acyloins.
  • the keto- (or aldehyde) groups can most importantly be derivatized by acetal formation, condensation, e.g. to imines, etc., or alkenylation, e.g. by reactions of the Wittig type.
  • acyloins It is a common property of all ⁇ -monosubstituted acyloins and their derivatives that they have a chiral centre on the ⁇ -(OH)-Carbon atom, i.e. in the ⁇ -hydroxy position, and this can easily be racemized by the neighbouring keto group.
  • an asymmetrically substituted acyloin is designated as an acyloin which bears different substituents R 1 and R 2 on the keto group and on the ⁇ -hydroxymethylene group, in other words, those compounds which form an acyloin of another structure as a result of an acyloin shift.
  • the nomenclature of the substituents is always in relation to the standard formula, not the shift version with exchanged keto and alcohol functions, which is only depicted here for the purposes of demonstration.
  • acyloins The preferred synthetic procedure for acyloins is by acyloin condensation from carboxylic acid derivatives or aldehydes, which is a procedure which is especially suitable for symmetrical acyloins.
  • Other procedures employ the oxidation of 1,2-diols and the reduction of 1,2-dioxo compounds. The latter methods have also been performed asymetrically and enzymatically (see e.g., Bioorg. Chemistry 21, 1993, 342; Bull. Chem. Soc. Jpn. 1994, 3314; J. Chem. Soc., Perkin Trans I1991, 1329, ibid. 1996, 425; J. Chem. Soc., Chem. Commun. 1993; 341, J. Org. Chem.
  • Acyloins and their derivatives are also excellent building blocks for the synthesis of epothilones, where the acyloin unit is mainly found as carbon atoms C15 and C16, in accordance with the epothilone numbering system given below.
  • Epothilones are naturally occurring substances with extraordinary biological activity, for example as mitosis inhibitors, compounds which affect microtubular activity, cytotoxic agents and fungicides. In particular, they possess paclitaxel-like properties and even surpass the activity of paclitaxel (Taxol®) in some tests. They are now being examined in clinical studies on the treatment of cancer.
  • Epothilone in particular epothilones B and D, possess a C7-C18(methyl) unit in the “north moiety”, which corresponds to a modified polyprenyl- (polyisoprene-) chain, and can for example be synthesized in accordance with the German Patent Applications No. 197 13 970.1 and No. 100 51 136.8. There is also a C1-C6 (methyl) unit in the “south moiety”, which can be synthesized by aldole type reactions, e.g. in accordance with German Patent Application No. 197 01 758.4, (1998).
  • allyl compounds including prenyl derivatives, have usually been synthesized for the production of the structural element C7-C21 of the epothilones or of subunits, especially C7-C15/16 and C11-C15/16 structural units, where the allyl compounds were coupled with C15-C16 methyl structural units which were difficult to access or in the wrong oxidation state.
  • Racemates are usually produced in the method for the production of the epothilone north moiety, in which the oxidation state at C15 and C16 is correct for epothilone synthesis, in particular, in accordance with German Patent Application 100 51 136.8. Therefore, all known methods for the synthesis of the epothilone north moiety exhibit the disadvantage that an asymmetric synthesis can only be performed with difficulty.
  • ⁇ -Hydroxyketones with at least one chiral centre on the ⁇ -hydroxy position are therefore important precursors of biologically active substances, such as polyketides and terpenoids and, in particular, epothilones and their derivatives.
  • An economic production method is therefore of great significance.
  • An optimal and economic, possibly enzymatically catalyzed, production of acyloins which are not racemic at the ⁇ -hydroxy position should advantageously fulfil a series of conditions, such as for example high enantioselectivity, relative to the ⁇ -hydroxy position of the acyloin, high selectivity for diastereomers, good yield in space and time (short reaction times, high degree of conversion of the enantiomer, high educt and product concentrations), low substrate specificity for the enzyme, high chemical yield of the desired product, low quantities of catalysts (especially of enzymes), easy purification of the synthetic products, good solubility of educt and product under the reaction conditions and cheap synthesis, i.e. easily synthesizable educts, easy handling of the educts, reagents and enzymes.
  • a further object of the present invention is to overcome the disadvantages in the state of the art in the synthesis of the structural elements C1-C6 or C7-C16 of the epitholones which were described above, and in particular to provide less demanding and cheaper procedures which are as free as possible from side-reactions and with which the desired structural elements are made available at yields which are as high as possible.
  • the compound according to the invention is not racemic, i.e. is optically active at the ⁇ -hydroxy position of the general formula I.
  • the compounds in accordance with the invention are in this embodiment particularly suitable for the economic synthesis of polyketides and terpenoids, in particular of epothilones and their derivatives, since a high enantioselectivity and diastereomeric selectivity is guaranteed in this way, which, in particular, makes clinical use of the final products possible.
  • Residue R 2 in general formula I is preferably selected from the group consisting of propinyl-, propargyl- and allyl residues.
  • residue R 2 in the general formula I is an alkylpropinyl residue and the compound is racemic and/or not racemic at the ⁇ -hydroxy position of the general formula I.
  • residue R 2 in the general formula I is an allyl residue
  • R 2 is selected from the group consisting of 3-alkylallyl, 3,3-dialkylallyl, E- or Z-3-halogenallyl and 3,3-dihalogenallyl.
  • residue R 2 in the general formula I contains an allyl derivative of type A (coupled to formula I at X):
  • residue R 2 or A is selected from the group consisting of a neryl and a geranyl residue, especially from the group consisting of a neryl or geranyl derivative which is oxidized at the ⁇ -position to an alcohol, aldehyde or carboxylic acid and/or ⁇ -1/2-hydrated.
  • residue R 2 can therefore be selected from the group consisting of an ⁇ -hydroxy- and an ⁇ -oxo- ⁇ -1/2)-dihydroneryl residue.
  • the ⁇ -hydroxy group of the general formula I is protected by a protecting group PG, particularly an acyl group. It is especially preferred that the protecting group, PG, is selected from the group consisting of the acetyl, propionyl, butyroyl and benzoyl groups.
  • a compound is made available in which the ⁇ -hydroxy group of the general formula I is protected by a non-racemic chiral acyl group, where
  • the ⁇ -hydroxy group of the general formula I is protected by a non-racemic chiral acyl group selected from the group consisting of 2-alkoxy and 2-(N,N-di-PG-amino)acyl groups.
  • Esterification of the ⁇ -hydroxy group of general formula I with optically active 2-alkoxymandelic acid or with 2-alkoxylactic acid and, especially, 2-methoxymandelic acid as non-racemic protecting group is particularly preferred.
  • non-racemic chiral protecting groups in particular non-racemic chiral acyl groups, are known to the person skilled in the art.
  • acyloins or acyloin derivatives which contain an Evans type auxiliary group as described above in accordance with the invention, it is also possible to carry out enantiomerically enriched synthesis of polyketides and terpenoids, epothilones and/or their derivatives.
  • the Evans-type auxiliary, Aux-N* is preferably an optically active oxazolidinone or N-methylimidazolidinone with the general formula where
  • the Evans type auxiliary may be derived from ephedrines.
  • a compound of this type with the general formula V in particular when it is not racemic, i.e. is optically active at the ⁇ -position and/or Z is a carbonyl residue, is an especially preferred structural element for epothilone synthesis.
  • residues R 2 are provided on their site of coupling with, preferably, H; OH; or halogen or other conventional leaving groups and their combinations; preferably Cl, Br, I, O-tosyl, methylsulfonate, trifluormethylsulfonate, alkanoate and, arylcarboxylate; and especially preferred H, Cl, Br.
  • step c) of the procedure according to the invention is carried out by hydrolysis with water and/or transesterification with alcohols.
  • Possible catalysts for the solvolysis in step c) are basic, acid and/or Lewis acid catalysts.
  • the catalysts are preferably selected from the group consisting of alkali hydroxides, alkaline earth hydroxides, alkali hydrogen carbonates, alkaline earth hydrogen carbonates, alkali carbonates, alkaline earth carbonates, inorganic acids, organic acids, especially aromatic sulfonic acids or polymer-bound acids, and Lewis acid catalysts such as lanthanide salts, titanium salts, in particular titanium(IV) alkoxides.
  • Suitable solvents are known to the person skilled in the art. Examples will be given below in connection with other methods according to the invention for the synthesis of synthetic building blocks for the synthesis of epothilones.
  • the reaction temperature lies in the range from ⁇ 80° C. to 150° C., depending on the reactivity and solvent system, preferably however in the range from 0° C. to 90° C., and particularly preferably in the range from 15° C. to 35° C.
  • the preparation is usually carried out by shaking out with conventional organic solvents, drying and possibly purification by distillation, crystallization and/or chromatography.
  • the solvolysis in step c) is performed by mildly basic hydrolysis with mildly basic catalysts, preferably in aqueous and/or alcoholic solutions, with higher alkali carbonates or dilute alkali hydroxides as catalysts, and the dosage during the reaction should preferably be adjusted during the reaction so that the pH value does not exceed that of a carbonate solution.
  • the reaction is carried out preferably in methanol or ethanol with aqueous sodium or potassium carbonate solution.
  • Racemate separation has as yet only been rarely performed on acyloins, almost exclusively on symmetrical acyloins, without problems related to the acyloin shift or with inferior results with respect to the purity of the enantiomers and/or yield and/or specific rotation, and/or greater difficulty than in the procedure described below (see e.g. J. Chem. Soc. Chem. Commun. 1997, 1399; Tetrahedron: Asymmetry 10, 1996, 2207; ibid. 1997, 2773; Tetrahedron Lett. 1997, 6429). Moreover, there are few examples of racemate separation for homoallylalcohols (e.g. Tetrahedron: Asymmetry 10, 1999, 315).
  • the ⁇ -hydroxy group can be esterified with optically active 2-alkoxymandelic acid or 2-alkoxylactic acid, and preferably with 2-methoxymandelic acid.
  • the production of compounds of the general formula I which are non-racemic at the ⁇ -hydroxy position is performed through intermediate products in the form of compounds of the general formula VI with possible subsequent purification by chromatography, where PG′ is selected from the group consisting of H and protecting groups, which do not react during the conventional enolization of the auxiliary modified intermediates and which is preferably selected from the group consisting of silyl, benzyl and oxymethyl derivatives.
  • the compounds with the general formula VI are in particular provided by conversion of non-racemic 4- and/or 5-substituted N—[O-PG]-acetyl-N-methylimidazolidinones, in which PG is a protecting group, with ⁇ -hydroxyketone compounds, possibly in the presence of base, preferably lithium dialkylamides and/or alkali hexamethyldisilazides.
  • the ⁇ -hydroxyketone compounds include the residue R 2 , in particular the residue Y, where neryl derivatives are especially preferred, and suitable leaving groups X.
  • the purification and possible separation of the diastereomers occurs preferably by liquid chromatographic separation on achiral solid phases such as silica gel.
  • organometallic compounds preferably of alkyllithium or alkylmagnesium compounds, especially preferred being methyl- or ethyllithium or methyl or ethyl Grignard reagents, to compounds of the general formula VI.
  • racemic free acyloin can be enzymatically esterified to O-acylacyloins, with partial, preferably predominant and especially preferably almost complete, separation of the racemate.
  • a further alternative and especially preferred embodiment of the method in accordance with the invention is the production of compounds of the general formulae I or IV, which are non-racemic at the ⁇ -hydroxy position, by separation of the racemates by enzymatic esterification of compounds of the type I.
  • esterification is carried out with an active ester, preferably isopropenyl and/or vinyl acetate.
  • the enzymes which catalyze the esterification are preferably selected from the group consisting of lipases and esterases, for example lipases from Pseudomonas cepacia and/or Candida antarctica.
  • esterases from Pseudomonas fluorescens and/or Streptomyces diastatochromogenes are used.
  • a solution of the acyloin in a suitable organic solvent preferably an alkane, especially preferred toluene
  • a lipase or esterase which may be immobilised or processed in another manner, preferably a lipase
  • an active ester preferably isopropenyl or vinyl acetate, especially preferred at a slight excess; preferably at 10-70° C., especially preferred at the enzymatic optimum or in a range plus/minus 10° C. round the enzymatic optimum, possibly with shaking, preferably with shear-free stirring or shaking, until the desired conversion has taken place.
  • the reaction is ended by preparation, preferably by centrifugation, the solvent is taken off and removed by vacuum distillation.
  • the ester and unreacted free acyloin can be separated by distillation, crystallization or chromatography, preferably solid phase chromatography, e.g. silica gel or aluminium oxide.
  • the enzyme catalysing the hydrolysis is preferably selected from the group consisting of lipases and esterases.
  • the lipases from Pseudomonas cepacia and/or Candida antarctica can be used.
  • esterases from Pseudomonas fluorescens and/or Streptomyces diastatochromogenes are advantageous. Recombinant pig liver esterase is especially preferred.
  • an ester of general formula IV is dissolved or suspended in a buffer, preferably a phosphate or carbonate buffer; the hydrolase, preferably a lipase or esterase, possibly in an immobilized or other processed form, is then added.
  • buffering can be carried out, preferably by the pH-controlled addition of base.
  • the pH value depends on the known or determined optimum and threshold values of the enzyme, where a pH value between these values is ideal when it allows optimal reaction control.
  • the reaction is carried out preferably between 10-70° C., especially preferably at the enzymatic optimum or within plus/minus 10° C. of the enzymatic optimum, until the desired conversion has taken place, possibly with shaking, preferably with shear-free stirring or shaking.
  • the reaction is performed with a conversion of 50% (relative to racemate), possibly somewhat under this or more rarely above this, if this serves the higher optical purity of the target product (alcohol or ester).
  • the preparation is performed with suitable organic solvents which are non-miscible with water (esters, ethers, aromatic compounds, even simple alkanes if the product is soluble), preferably ethyl acetate or toluene.
  • the extraction yield can be raised by the previous addition of small quantities of acetone or other solubilizers or by the previous removal of the enzyme by centrifugation.
  • the preparation and purification follows the usual processes, which are also described above.
  • lipase CAL-B has a temperature optimum of 60° C. and can be used at temperatures of up to 70° C. without problems.
  • Another possible preferred temperature range for the procedures in accordance with the invention is e.g. 20° C.-45° C.
  • diastereomeric separation is performed of compounds of the general formula I, II, III, IV and/or V, of which the ⁇ -hydroxy group is protected with a non-racemic chiral acyl group (R 3 ⁇ R*).
  • the separation of the diastercomers can for example be performed by crystallization, cocrystallization, distillation, sequential extraction, e.g., HSCCC (high speed counter current chromatography) and/or chromatographic separation, preferably by chromatographic separation, especially preferred being a liquid chromatographic procedure on achiral solid phases such as silica gel.
  • compounds of the general formula IV are converted to compounds of the general formula V: where Z is selected from the group consisting of: ⁇ O, ⁇ N-Nu, ⁇ CH-hetaryl, ⁇ CH-aryl and ⁇ PR 3 ; and is preferably ⁇ CH-hetaryl; and is especially preferably selected from the group consisting of (E)-(2-methylthiazol-4-yl)-CH ⁇ and (E)-(2-methyloxazol-4-yl)-CH ⁇ ; where all groups Z may be present in the (E)-form, (Z)-form or as a (E/Z) mixture.
  • the conversion is performed preferably by reactions of the Wittig type, as known to the person skilled in the art. Conversion to a compound with the general formula: is particularly preferred.
  • the compounds of general formula I, II, IV and/or V are racemized under water-free and strongly basic conditions, preferably with the bases trialkylamine, DBU, DBN and/or polymeric strong bases. This enables a recirculation to carry out racemate separation.
  • free or protected acyloin is dissolved in a water-free organic solvent, preferably an alkane, ether and/or aromatic compound and base added.
  • a water-free organic solvent preferably an alkane, ether and/or aromatic compound and base added.
  • the temperature preferably 0° C. to 65° C., especially preferably 25° C. to 40° C., can be raised to the boiling point of the solvent to increase the rate of isomerization, if this does not lead to marked side-reactions.
  • the reaction mixture is filtered through silica gel or washed with acid or stirred with scavenger resin to remove the basic catalyst.
  • a further object of the present invention is the use of the compounds in accordance with the invention as building block, in particular as C 15 -C 16 containing building block for the production of epothilones and their derivatives.
  • Another object of the present invention is the use of the procedure according to the invention in the production of epothilones and their derivatives.
  • the structural elements with the general formulae I and V can preferably be used as products or as intermediates in the synthesis of active substances or drugs.
  • the structural elements with the general formulae I to V in accordance with the invention can be used for the synthesis of polyketide and terpenoid natural products, preferably, as with structural elements of the general formula V, for the synthesis of macrocyclic substances, such as epothilones and their derivatives, including stereoisomers and/or homologues, nor-compounds, and/or as fully or partially inverted elements, in which they can preferably serve as C15/C16 building blocks, as C12-C16 building blocks, as C11-C16 and C7-C16 building blocks or, especially preferably, as C7-C16(Me)-building blocks of the ring, which may additionally already contain preformed elements or the complete side chain C15 or C16 of the ring.
  • macrocyclic substances such as epothilones and their derivatives, including stereoisomers and/or homologues, nor-compounds, and/or as fully or partially inverted elements, in which they can preferably serve as C15/C16 building blocks,
  • the synthetic building blocks are preferably enriched in an enantiomeric and/or diastereomeric form, especially preferably in the absolute configuration corresponding to that of the natural epothilones.
  • compounds in accordance with the general formulae I, IV and V are made available, in which the functional groups are fully or partially protected by PG.
  • the compounds in accordance with the invention with the general formulae I, II, III, IV and V may, in accordance with the invention, for example, be prepared in optically active form on C15 (or on C16 by the shift-acyloins) by asymmetric synthesis with alkoxyacetyl compounds coupled to Evans-type auxiliaries, by formation of diastereomers, followed by separation with optically active acids and their derivatives and by racemate separation by enzymatic hydrolysis or esterification; preferably with one of the latter two procedures; especially preferably with the enzymatic procedure.
  • the compounds in accordance with the invention with the general formulae I, II, III, IV and V generally contain at least one substituent in the lowest C-position which is suitable to make coupling with other building blocks of epithilone possible, e.g. on C7 especially with C1-C6 building blocks, as given in the German Patent Application DE 197 01 758.4.
  • Alkyl designates hydrocarbon residues, also branched isomers, with preferably 1 to 8 carbon atoms.
  • Aryl designates phenyl, naphthyl, benzyl and their derivatives with up to five alkyl-, alkoxy- or halogen substituents, however preferably those with up to three substituents, especially preferably with up to one substituent; preferred are corresponding phenyl and benzyl derivatives; and combinations of these.
  • Hetaryl or heteroaryl designates five and six membered heteroaromatic compounds with one or several O, S, and N-atoms; and their derivatives with up to four alkyl, alkoxy or halogen substituents, however preferably those with up to two substituents, especially preferably with up to one substituent; preferred are corresponding oxazole, thiazole and pyrimidine derivatives; especially preferably alkylthiazole and oxazole derivatives; and combinations of these.
  • PG designates the conventional protective groups for the given coupling atom or the given functional groups, e.g. as in the book G REENE /W UTS 1991 (Protective Groups in Organic Synthesis, ISBN 0-471-62301-6), such as allyl, t-Butyl, methyl, benzyl, silyl, acyl or activated methylene derivatives such as methoxymethyl, alkoxyalkyl or 2-oxacycloalkyl protective groups; preferably—predominantly for alcohol and amine functions—trimethylsilyl, triethylsilyl, dimethyl-tertbutylsilyl, acetyl, propionyl, benzoyl, tetrahydropyranyl.
  • PG′ are then those groups which do not react during the conventional enolization of the auxiliary-modified intermediates (e.g. with LDA), such as silyl, benzyl or oxymethyl derivatives in accordance with the above literature.
  • auxiliary-modified intermediates e.g. with LDA
  • trifluorethyl esters trifluorethyl esters
  • oxime esters or thioesters preferably alkenyl esters, especially preferably O-vinyl and O-isopropenyl.
  • a further essential aspect of the present invention relates to epothilone building blocks for the north and south moieties of epithilones and procedures for their production and coupling.
  • the compounds provided by the present invention are suitable as building blocks for the synthesis of polyketiden, terpenoids, epothilones and/or their derivatives.
  • Examples for the epothilone synthesis building blocks in accordance with the invention are selected from the group consisting of compounds with the general formulae VII, X, Xa, XI, XIa, XII, XIII, XVa and XVb.
  • Aryl is selected from the group consisting of phenyl, naphthyl, benzyl and their derivatives; preferably with up to five alkyl, alkoxy or halogen substituents, especially preferred being those with up to three substituents, and most preferred being those with up to one substituent; and preferably selected from the group consisting of phenyl and benzyl derivatives and combinations of these.
  • Hetaryl/heteroaryl is selected from the group consisting of five and six membered heteroaromatic compounds with one or several O-, S- and N-atoms; and their derivatives with up to four alkyl, alkoxy and/or halogen substituents; preferably those with up to two substituents, especially preferably with up to one substituent; preferably selected from the group consisting of oxazole, thiazole and pyrimidine derivatives; and where an alkylthiazole derivative is specially preferred; and combinations of these.
  • PG is a protecting group, preferably selected from the group consisting of allyl, methyl, t-Butyl (preferably at EWG), benzyl, silyl, acyl and activated methylene derivatives such as methoxymethyl, alkoxyalkyl and 2-oxacycloalkyl; preferably—predominantly for alcohol and amine functions—selected from the group consisting of trimethylsilyl, triethylsilyl, dimethyl-tertbutylsilyl, acetyl, propionyl, benzoyl, tetrahydropyranyl; and from protecting groups which protect neighbouring or bivalent groups (PG 2 ) simultaneously by forming 5-7 membered rings, such as succinyl, phthalyl, methylene, acetonide and/or combinations of all the above protecting groups.
  • protecting groups which protect neighbouring or bivalent groups (PG 2 ) simultaneously by forming 5-7 membered rings, such as succinyl, phthaly
  • E is preferably CH 2 X, CO 2 PG and/or CHO and especially preferably CHO.
  • EWG H; and X H and/or halogen. It is particularly preferred that EWG is selected from the group consisting of Cl, Br and I.
  • substituent Y—CO—CRR′X is replaced by an OH— or NH 2 — group, preferably by OH.
  • B 3 is a single or double bond as E-(trans) form, Z-(cis) form or a E/Z mixture; preferably a single or double bond to heteroatoms such as O, S or N, especially preferably a single bond to O-PG or OH;
  • R is selected from a group consisting of H, methyl, ethyl, propyl, phenyl, benzyl; preferably selected from a group consisting of H, methyl, ethyl and combinations of these;
  • R′′ is selected from the same group as R and methyl is particularly preferred.
  • the term derivatives includes homologous, analogous and nor-compounds, preferably also variants with further substituents on the main chain or in the C15-C16 element.
  • the stereochemistry of the starting material (E- or Z-prenyl compound) can be used to predetermine the stereochemistry on C12-C13.
  • X is preferably OH, OAc, OTs, Cl and/or Br.
  • OTs, Cl, Br are especially preferably used as electrophilic building blocks.
  • Synthetic building blocks prepared according to the invention have, among other characteristics, the general structural formula VII, preferably the formula VIIa, especially preferably the formula VIIb, and may be present in the racemic or non-racemic forms, or as individual diastereomers or as a mixture of diastereomers.
  • the structural elements VII and X can be preferably used as products or as intermediates in the synthesis of active substances.
  • the structural elements VII in accordance with the invention can be used for the synthesis of polyketide and terpenoid natural products or derivatives of polyketide and terpenoid natural products, preferably for macrocyclic active substances such as epothilones and their derivatives, including stereoisomers and/or homologues, nor-compounds, and/or can serve as fully or partially inverted elements, in which they serve preferably as C7-C15 and C7-C16 or especially preferably as C7-C14 structural elements of the ring, which additionally may already bear preformed elements or the complete side chain on C15.
  • building blocks are referred to below as synthetic building blocks and are preferably enriched in an enantiomeric and/or diastereomeric form, the forms which correspond to those in the natural epothilones.
  • the compounds of type VII in accordance with the invention and their stereoisomers can be obtained for example starting with commercially available starting materials VIII and/or IX, which may also be prepared by known procedures, by C—C coupling with 2-oxy-substituted 1,3-diactivated methylene compounds with the general formula X, preferably with 2-acyloxy-1,3-dicarbonyl compounds, especially preferably with 2-acyloxyacetoacetates, specifically preferably with compounds of formula Xa, where basic reaction conditions are of particular advantage.
  • sensitive positions which are not to be oxidized can be protected in the conventional and well known manner (see below).
  • alcohols are preferably protected as silyl ethers or alkanoates and carboxylic acid groups preferably as esters.
  • the oxidation is carried out according to the instructions, as they are listed for example in H UDLICKY 1990 (Oxidations in Organic Chemistry, 0-8412-1781-5/90).
  • the 7 position is preferably oxidized, preferably with selenium reagents, especially preferably with selenium dioxide or peroxides.
  • allylalcohols from commercial prenylalcohols or prepared as above can be converted into an active form according to known procedures, preferably into allylhalides, -sulfonates or carboxylates, especially preferably into C7- and C14-halides of the compounds VII or VIII and protected derivatives of these.
  • the C8-C9 double bond can be selectively reduced.
  • a remaining C12-C13 double bond can, for example, be selectively epoxidated with peroxyacids.
  • E tert-butylcarboxylates
  • nucleophiles may be selectively introduced into position 9 with the Michael reaction, where simple alkyl cuprates, alcohols and amines are preferred.
  • These compounds can also be coupled with C1-C6 building blocks.
  • Suitable protecting groups are: allyl, benzyl, methyl, ethyl, t-butyl, activated methylene derivatives such as methoxymethyl, 1-oxacycloalkyl, silyl, in particular trialkylsilyl; and—predominantly for alcohol functions—also acyl protecting groups, preferably acetyl, propionyl and benzoyl and their derivatives.
  • Protecting groups are also preferred which simultaneously protect neighbouring groups Y, for example acetonides, methylene, cyclodiacyl and those which protect carbonyl groups, in particular acetals and cyclic acetals (O and S).
  • Other protecting groups which are suitable for the procedure in accordance with the invention are described in G REENE /W UTS 1991 (Protective Groups in Organic Synthesis), which is expressly referred to. Combinations of these protecting groups are also possible and advantageous, depending on the approach.
  • compounds of type XI are also suitable C3-C6 building blocks and that these can for example be prepared by reaction of 2-haloacylhalides with the enamine of isobutyraldehyde, followed by hydrolysis and acetal formation.
  • compounds of the type XII or XIII activated in the C6 position may easily be obtained from compounds of type XIII and XIa by oxidation, especially by electrophilic halogenation, especially preferably with tertiary or quaternary ammonium perhalides. These reactions are very easy and give good yields.
  • reaction i.e. the reaction with compounds of the general formula VII
  • the reaction occurs to an extraordinarily high degree with syn-selectivity and aldehyde-selective, which makes it possible to react substances of type VII in an efficient manner, especially those in which Z is a ketone or a hetarylalkylidene side chain.
  • a particular advantage of the procedure in accordance with the invention is that the functionalities may be used without protection to a large extent. Thus, for example, a free ester group may be used at C1 and a free keto group at C16.
  • a significant aspect of the present invention relates to the coupling of north and south moieties.
  • north and south moieties may be coupled, or—in case of preesterized components—be cyclicized by aldole reactions, preferably of the Reformatsy type, especially preferred with chromium(II) salts, between C6-C7 or C2-C3, or successively on both sites, using the previously described methods which are described in the following and in detail particularly in the examples.
  • Open chain compounds may be cyclicized by macrolactonization according to known methods.
  • the previously named substituents, protecting groups, bond types B and/or stereo isomers, as well as the order of coupling or modification may be changed or combined arbitrarily, if chemically reasonable.
  • the compounds with the general formulae VII, VIII, X and/or XI are racemized under anhydrous, strongly alkaline conditions, preferably with the bases trialkylamine, DBU, DBN, and/or polymeric strong bases.
  • a further embodiment of the methods according to the invention for the production of compounds according to the formula VII comprises the reaction of prenylene compounds, electrophilically activated in ⁇ and/or ⁇ position, composed of 1-4 prenyl units with compounds according to the general formula X.
  • prenylene compounds electrophilically activated in ⁇ and/or ⁇ position, are selected from the group consisting of prenyl alcohols, acetates, halides, compounds with the general formula VIII, compounds with the general formula IX, and functionalized and/or protected prenyl derivatives with the general formula XIV, where
  • the prenyl compounds are converted by C—C coupling using nucleophilic substitution with 2-oxy-substituted, 1,3-di-activated methylene compounds according to the formula X, preferably 2-acyloxy-1,3-dicarbonyl compounds, particularly preferred with 2-acyloxy-acetoacetates, most of all preferred with compounds according to formula Xa, preferably in presence of one or more bases, adding a solvent where applicable, and/or in the presence of modifiers.
  • the reaction temperature usually ranges from ⁇ 80° C. to +180° C., preferably from ⁇ 30° C. to +100° C., and particularly preferred from ⁇ 5° C. to +80° C.
  • Suitable bases are usually selected from the group comprising alkali metals, hydridic bases, nitrogen bases in neutral or negatively charged form, alcoholates, hydroxides, carbonates, hydrogencarbonates, and carban ions; preferably comprising hydridic bases, nitrogen bases, carbonates, hydrogencarbonates, and particularly preferred comprising hydridic bases, carbonates, and/or hydroxides of the alkali or alkali earth metals, such as NaH, KH, and LiH.
  • Suitable solvents are selected for example from the group comprising hydrocarbons, alkanes, benzene, and alkylized derivatives therefrom, ether, dichlormethane, chloroform, tetrachlorcarbon, chlorated aromates, alcohols, ketones, sulfoxides such as DMSO and sulfolane, carbon acid amids, alkylated carbon acid amids, sulfolane, DMPU, glymes, alkyl and aryl nitrites, carbon acid esters, tertiary amines and/or mixtures thereof, preferably comprising carbon acid amids and alkylated carbon acid amids, ketones, sulfoxides such as DMSO, and sulfolane, alcohols, alkyl and/or aryl nitrites; and particularly preferred comprising carbon acid amids, alkylated carbon acid amids, ketones, sulfoxide, DMSO, sulfolane and/or alcohols.
  • a further subject of the present invention are methods for synthesizing compounds with the general formula XI.
  • a further subject of the present invention are methods for synthesizing compounds with the general formula XII.
  • Such methods comprise reacting a compound with the general formula XIII with a reagent selected from the group consisting of halogenization reagents, and electrophilic oxygen reagents in a suitable solvent, if applicable adding acidic or alkaline modifiers.
  • Suitable halogenization reagents are for example electrophilic halogenization reagents, preferably selected from the group consisting of primary halogens; halogenimide derivatives; sulfur(oxy)halides such as sulfurylchloride; perhaloalkanes, and ammonium perhalides; and particularly preferred being selected from the group consisting of tertiary and quarternary ammonium perhalides such as pyridinium bromide perbromide, trimethyl phenyl ammonium bromide perbromide, and/or polymer-bound variants of the previously mentioned reagents.
  • electrophilic halogenization reagents preferably selected from the group consisting of primary halogens; halogenimide derivatives; sulfur(oxy)halides such as sulfurylchloride; perhaloalkanes, and ammonium perhalides; and particularly preferred being selected from the group consisting of tertiary and quarternary ammonium perhalides such as pyridin
  • the reaction temperature in the latter mentioned method is usually from ⁇ 80 to +160° C.; preferably from ⁇ 30 to +65° C.; and particularly preferred from ⁇ 5 to +10° C.
  • Suitable solvents are usually selected from the group consisting of etheric and halogenized solvents; being preferably selected from the group consisting of diethylether, THF, chloroform, dichlormethane, liquid carbon acid amids and esters; and being preferably selected from the group consisting of DMF, DMA, acidic acid ester, liquid sulfoxides such as DMSO and sulfolane.
  • a further subject of the present invention are methods for synthesizing compounds with the general formulae XVa and/or XVb.
  • Such methods comprise reacting compounds VII with compounds of type XI or XIa; XII; and/or XIII.
  • Preferred are such compounds XV in which all carbon atoms of the epothilone macrocycle XVI are present.
  • Most preferred are such compounds XV bearing a halogen at C2 and/or C6.
  • reaction temperature ranges usually from ⁇ 80° C. to +140° C.; being preferably higher than 0° to 65° C., and particularly preferred being from 15° C. to 35° C.
  • Suitable metals are usually selected from the group consisting of Li, Mg, Zn, In, Mn, Fe (each in activated form); and suitable metal salts, preferably anorganic or organic salts; complexes and/or organometal complexes of the metal ions Ti(II), Ti(III), Cr(II), Sm(II), Co(I), V(II) and Fe(II), particularly preferably halides, sulfates, sulfonates, alkanoates, cyclopentadienylates and phenylates; solid phase or polymer-bound metal salts; and combinations therefrom; and preferably selected from the group consisting of zinc, titanium(II) and Cr(II) compounds, particularly as chloride, bromide, acetate, sulfate, generated in situ or polymer-bound.
  • Suitable catalysts are selected from the group consisting of iodides; unreducable Lewis acids, such as lithium salts, aluminum chloride, boron trifluoride, and/or Lewis acids generated in situ during the formation of reducing metal salts with LiAlH 4 ; nickel(II) salts; nucleophilic and/or redoxactive metal complexes, such as vitamin B12 and comparable, synthetic Co complexes.
  • the suitable catalysts are present preferably in amidic solvents and/or sulfolane; and it is also preferred that up to 33 mol % of the anhydrous catalyst, preferably 0.01-5 mol % reactive Lewis acids, is added, if applicable mixed with a suitable metal salt, preferably prior to the addition of the solvent.
  • the modifiers are preferably selected from the group consisting of iodides (metal iodides MI); unreducable, usual Lewis acids such as lithium salts; aluminium chloride, boron trifluoride, complexing ligands, particularly also chiral ligands, particularly preferred bidentate ligands and other usual ligands; and combinations therefrom; and are preferably also in an anhydrous condition.
  • iodides metal iodides MI
  • unreducable, usual Lewis acids such as lithium salts
  • aluminium chloride boron trifluoride
  • complexing ligands particularly also chiral ligands, particularly preferred bidentate ligands and other usual ligands
  • modifiers from the group consisting of anhydrous lithium oxide, sodium iodide and aluminium chloride.
  • Suitable solvents are usually selected from the group consisting of hydrocarbons such as alkanes, benzene, and alkylated derivatives; ethers; dichlormethane; chloroform; chlorated aromates; sec./tert. alcohols; ketones; dimethylsulfoxide; carbon acid amids; alkylated carbon acid amids, sulfolane; DMPU; glymes; alkyl and aryl nitriles; carbon acid esters; tertiary amines and mixtures thereof; and are preferably selected from the group consisting of methyl-tert.-butylether, diethylether, tetrahydrofurane, glymes, sulfolane, DMSO, ketones up to C5, dimethylformamide and -acetamide, acetonitrile and mixtures thereof; and should particularly preferably be anhydrous solvents.
  • hydrocarbons such as alkanes, benzene, and alkylated derivatives
  • the methods according to the invention preferably comprise reacting one or more metal salts by reduction with a reducing agent at an oxidation level suitable for the method; the reaction being performed preferably in situ, or prior to the synthesis of the compound with the general formula XVa.
  • Suitable reducing agents or methods are, for example, selected from the group consisting of electrochemical methods, lithiumaluminiumhydrid, and comparable hydrids, metalic iron or manganese in their various forms, and are preferably selected from the group consisting of lithiumaluminiumhydrid and zinc.
  • the reaction temperature of this method according to the invention usually ranges from ⁇ 50° C. to +160° C., preferably over 0° to 100° C., and particularly preferred from 15° C. to 55° C.
  • Esterification and/or transesterification catalysts are e.g. selected from the group consisting of bases, acids, and metal alcoholates such as titaniumtetraalcoholate, which are generally used for this purpose.
  • coupling reagents preferably selected from the group comprising EDCI, DCC/DMAP, and/or methods such as the Yamaguchi esterification are used in particular.
  • suitable solvents are usually selected from the group consisting of hydrocarbons such as alkanes, benzene and alkylated derivatives; ethers; dichlormethane; chloroform; chlorated aromates; carbon acid amides; alkylated carbon acid amides; sulfolane; DMPU; glymes; alkyl and arylnitriles; carbon acid esters; tertiary amines; and mixtures thereof; and are preferably selected from the group consisting of methyl-tert.-butylether, diethylether, tetrahydrofurane, glymes, sulfolane, chloroform, dichlormethane and/or mixtures thereof; and are particularly preferably selected from the group consisting of chloroform and dichlormethane.
  • hydrocarbons such as alkanes, benzene and alkylated derivatives
  • ethers such as alkanes, benzene and alkylated derivatives
  • the solvents should be anhydrous.
  • the oxidation means are used preferably catalytically. Alternatively, oxidation may occur bacterially or enzymatically with cell systems, with oxidation using SeO 2 being particularly preferred.
  • a further subject of the present invention relates to methods for synthesizing a compound with the general formula VII and/or XV, comprising addition of a nucleophile or electrophile to one or more, or the reduction, epoxidation or cyclopropanization of one or more double bonds of a compound with the general formula VII and/or formula XV.
  • the method according to the invention preferably comprises the reduction of the C8-C9 double bond; epoxidation of the C12-C13 double bond and/or addition of a nucleophile to C9.
  • the method according to the invention preferably comprises also the asymetrical and/or catalytical hydration of the C8-C9 double bond.
  • a further aspect of the present invention relates to methods for synthesizing epothilone macrocycles and derivatives with the general formula XVI: wherein:
  • Reactions of the Reformatsky type within the scope of the present invention are reactions of halogene carbon acid esters or helogene ketones with aldehydes or ketones in presence of metals.
  • this type of reaction comprises metalorganical reaction steps, which enable a C—C coupling particularly at C2-C3 and/or C6-C7.
  • the invention in its embodiments is not limited to the aforementioned preferred embodiment examples. Rather, a plurality of variants are conceivable which use the presented solutions for basically different embodiments as well.
  • 630 mg (2.3 mmol) tert-butyl-2-acetoxy-2-acetyl-4-hexenoate is added to a suspension of 120 mg Lindlar catalyst in 50 ml ethylacetate, and is evacuated twice and put under light positive pressure in a hydrogen atmosphere. After stirring for 24 h, it is filtered with ethylacetate through Celite®, washed with saturated sodium hydrogencarbonate solution, dried with Na 2 SO 4 , filtered, and the solvent was removed in vacuo.
  • neryl bromide (3.40 g, 15.7 mmol) was added dropwise. After stirring for three hours at ⁇ 78° C., the cooling bath was removed, and stirred for 15 min at ambient temperature. After quenching with a saturated NH 4 Cl solution (25 ml), the organic solvent was removed in the vacuum, and the remaining aqueous phase was diluted with demin. water (25 ml). It was extracted three times with 75 ml Et 2 O, and the combined organic phases were dried over Na 2 SO 4 . Then, it was removed from the drying agent by filtration, and the solvent was removed in the vacuum.
  • Trimethyl aluminium solution (4.50 ml, 2 M in toluene, 9.00 mmol) was dropped slowly to a suspension of N,O-dimethyl-hydroxylamine-hydrochloride (878 mg, 9.00 mmol) in CH 2 Cl 2 (12 ml) at 0° C.
  • the mixture was stirred at ambient temperature for 15 min, and then was cooled to ⁇ 10° C.
  • Methyllithium-lithiumbromide complex (1.87 ml, 1.5 M in THF, 2.80 mmol) was dropped to a solution of non-racemic 2-benzyloxy-N-methoxy-N,5,9-trimethyldeca-4(Z),8-dienoylamide (see above, 345 mg, 1.00 mmol) in CH 2 Cl 2 (15 ml) at ⁇ 78° C. It was stirred for 40 min at ⁇ 78° C., then the reaction mix was pumped through a stainless steel canula onto a mixture of saturated NH 4 Cl solution (20 ml), 14 ml hexane and 7 ml CH 2 Cl 2 cooled to 0° C. and intensively stirred.
  • the mixture was diluted with saturated NaCl solution (50 ml) and with a 3:1 hexane/CH 2 Cl 2 mixture (50 ml). Again, it was agitated intensively, and after phase separation, the aqeous phase was extracted again with CH 2 Cl 2 (30 ml). The combined organic phases were washed with saturated NaCl solution (150 ml) and dried over Na 2 SO 4 . Then it was removed from the drying agent by filtration, and the solvent was removed in the vacuum. The product was obtained with a high degree of purity.
  • Candida antarctica Novo lipase B ⁇ Chirazyme L2, CAL-B
  • Candida antarctica Novo lipase A, CAL-A
  • Candida rugosa Amano AY, CRL
  • Aspergillus niger Amano, ANL
  • Pseudomonas cepacia Amano PS, PCL-PS
  • Pseudomonas cepacia Amano AK, PCL-AK
  • Pseudomonas sp. Chorazyme L6, PSL).
  • AYS Candida rugosa
  • CAA Candida antartica A
  • CAB Candida antartica B
  • MJ Mucor javanicus
  • PS Pseudomonas cepacia
  • PPL porcine pancreas lipase.
  • rPLE Recombinant pig liver esterases
  • the ester is dissolved in methanol (e.g. 0.05-1M, generally approx. 0.13M); then, aqueous base is added (80 ⁇ l per mmol of ester), preferably—and if not mentioned separately—in saturated, aqueous potassium carbonate solution. After termination of the reaction (e.g. 30 min), saturated NaCl solution (approx. 1.5 ⁇ the volume of methanol) and a fivefold volume of ether is added. The organic phase is washed thoroughly with NaCl, dried with sodium sulfate, filtered, and the solvent is removed in vacuo. Further purification may be performed e.g. by silica gel chromatography.
  • Lipase or esterase e.g. approx. 20 mg
  • 0.7 ml phosphate buffer 0.1 M, pH 7.0
  • the acyloin ester e.g. 5 ⁇ l
  • a suitable vessel here e.g. a 1.5 ml Eppendorf® tube.
  • the mixture is agitated vigorously, and then mixed as usual (Vortex, 300 strokes/minute) at 0-60° C. depending on the enzyme, usually at room temperature.
  • the reaction is terminated by addition of acetone.
  • the process is controlled by a titrator or a polarimeter, or over time, usually in approx. 30 min.
  • Ethylacetate (0.4 ml) is added, separated by shaking and centrifuged (at 8.000 g for 5 min). The top organic layer is removed, and the rest is extracted again. The extraction may be also be achieved more difficultly without centrifugation. After drying of the combined organic phases over Na 2 SO 4 , a further centrifugation step may be performed (e.g. at 8.000 g for 5 min).
  • the ester was dissolved in 0.1 M phosphate buffer pH 7.0 (concentration approx. 0.07 M) and lipase was added (e.g. up to 25 vol % of the acyloin ester).
  • the reaction mix was shaken during the reaction until termination if the reaction (DC and GC control).
  • Acetone was added (1 ⁇ 2 of the buffer volume) and five times extracted with ethylacetate (1.5 ⁇ buffer volume).
  • hydrolase lipase or esterase
  • 1 ml sodium phosphate buffer pH 7.5, 50 nM
  • 200 ⁇ l substrate solution is added (10 mg/ml in toluene).
  • the reaction was stopped by centrifugation of the enzyme, the toluene layer was removed and analyzed (e.g. by GC, polarimetry).
  • the listed compounds may also be isomere mixtures, racemates, and/or diastereomers, if not mentioned explicitly otherwise.
  • Compounds enriched with enantiomeres are usually indicated by listing a rotation value. If desired, the resulting products were purified by purification procedures known in the art. 1.
  • N-bromo-succinimide (58.7 g, 330 mmol) was added in portions to a solution of tert-butyl acetoacetates (49.0 ml, 47.5 g, 300 mmol) in Acetone (30 ml). The resulting solution was stirred for one hour at ambient temperature, and subsequently filtered. The filtrate was vacuum concentrated, and the residuum was reconstituted in 300 ml petroleum ether. After washing three times, each time with 100 ml water, the solution was dried over Na 2 SO 4 and filtered. Then, the product was obtained by vacuum concentration. 2.
  • phenyl trimethyl ammonium bromide dibromide was added to a solution of 116 mg (0.383 mmol) (3S)-3-(tert-butyl-dimethyl-silanyloxy)-4,4-dimethyl-5-oxo-heptanoic acid in 3.8 ml tetrahydrofurane at 0° C. After stirring for fifteen minutes, the ice bath was removed, and stirring was performed for another hour at ambient temperature. 5.0 ml demin water was added to the resulting solution. The aqueous phase was extracted three times with 8 ml diethylether.
  • Procedure 1 A solution of acetic acid (10.6 mL, 186 mmol) in DMF (169 mL) was neutralised with triethylamine (25.8 mL, 186 mmol) at 0° C. To the resulting triethylammoniumacetate solution was added tert-butyl-2-bromo-acetoacetate (249) (40.0 g, 169 mmol) dropwise at 0° C. Then the icebath was removed and the reaction mixture stirred for two hours at room temperature. Quenching with water (280 mL) was followed by threefold extraction with ethyl acetate (3 ⁇ 215 mL).
  • Procedure 1 (from THP-ether): A solution of 238 mg (0.53 mmol) 3-acetoxy-11-(tetrahydro-pyran-2-yloxy)-2,6,10-trimethyl-1-(2-methyl-thiazol-4-yl)-undeca-1,5-diene (270b) and 13 mg (0.053 mmol) pyridinium paratoluenesulphonate in 5.0 mL 96% ethanol was stirred at 55° C. for eight hours. After concentration in vacuo, the residue was dissolved in 25 mL diethylether.
  • tert-butyl-2-acetoxy-aceto-acetate (219a) (1.08 g, 5.00 mmol), NaH (156 mg, 6.5 mmol) and ethylbromide (also propyl and pentyl) (373 ⁇ L, 549 mg, 5.00 mmol) were reacted in DMF (10 mL) to give 2-acetoxy-2-acetylbutanoic-acid-tert-butylester (250g) (970 mg, 3.97 mmol, 79%) as a slightly yellow oil.
  • tert-butyl-2-acetoxy-aceto-acetate (219a) (7.12 g, 32.9 mmol), NaH (900 mg, 37.5 mmol) and propylbromide (4.05 g, 32.9 mmol) were reacted in DMF (64 mL) to give 2-acetoxy-2-acetyl-pentanoic-acid-tert-butylester (250h) (6.00 g, 23.2 mmol, 71%) as a slightly yellow oil after Kugelrohr distillation at 160° C. and 1.0 mbar.
  • tert-butyl-2-acetoxy-aceto-acetate (219a) (1.08 g, 5.00 mmol), NaH (156 mg, 6.5 mmol) and butylbromide (538 ⁇ L, 685 mg, 5.00 mmol) were reacted in DMF (10 mL) to give 2-acetoxy-2-acetyl-hexanoic-acid-tert-butylester (250i) (1026 mg, 3.77 mmol, 75%) as a slightly yellow oil.
  • tert-butyl-2-acetoxy-aceto-acetate (219a) (7.12 g, 32.9 mmol), NaH (900 mg, 37.5 mmol) and pentylbromide (4.97 g, 32.9 mmol) were reacted in DMF (64 mL) to give 2-acetoxy-2-acetyl-heptanoic-acid-tert-butylester (250j) (6.40 g, 22.3 mmol, 68%) as a slightly yellow oil after Kugelrohr distillation at 185° C. and 1.0 mbar.
  • tert-butyl-2-acetoxy-aceto-acetate (219a) (1.08 g, 5.00 mmol)
  • NaH 156 mg, 6.5 mmol
  • hexylbromide 702 ⁇ L, 825 mg, 5.00 mmol
  • 2-acetoxy-2-acetyl-octanoic-acid-tert-butylester 250k

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  • Epoxy Compounds (AREA)
US10/414,510 2000-10-16 2003-04-15 Epothilone synthesis building blocks iii and iv: asymmetrically substituted acyloins and acyloin derivatives, methods for their production and methods for the production of epothilones b, d and epothilone derivatives Expired - Fee Related US6867333B2 (en)

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DE10051136A DE10051136A1 (de) 2000-10-16 2000-10-16 Epothilone-Synthesebausteine III und Verfahren zur Herstellung von Epothilon B, D und Epothilonderivaten
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DE10134172.5 2001-07-13
DE10134172A DE10134172A1 (de) 2001-07-13 2001-07-13 Epothilone-Synthesebausteine IV:Unsymmetrisch substituierte Acyloine und Acyloinderivate und Verfahren zu deren Herstellung
PCT/EP2001/011992 WO2002032844A2 (fr) 2000-10-16 2001-10-16 Composants synthetiques iii et iv d'epothilone : acyloines et derives d'acyloine a substitution asymetrique, leur procede de production et procede de production d'epothilone b, d et de derives d'epothilone

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US20080064634A1 (en) * 2006-05-01 2008-03-13 Markland Francis S Jr Combination therapy for treatment of cancer
US20090149516A1 (en) * 2002-08-23 2009-06-11 Danishefsky Samuel J Synthesis of Epothilones, Intermediates Thereto, Analogues and Uses Thereof
WO2009132253A1 (fr) 2008-04-24 2009-10-29 Bristol-Myers Squibb Company Utilisation de l'épothilone d dans le traitement des maladies associées à la protéine tau, y compris la maladie d'alzheimer
US8685668B2 (en) 2005-02-11 2014-04-01 University Of Southern California Method of expressing proteins with disulfide bridges
US8802394B2 (en) 2008-11-13 2014-08-12 Radu O. Minea Method of expressing proteins with disulfide bridges with enhanced yields and activity

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US6242469B1 (en) 1996-12-03 2001-06-05 Sloan-Kettering Institute For Cancer Research Synthesis of epothilones, intermediates thereto, analogues and uses thereof
US20020058286A1 (en) * 1999-02-24 2002-05-16 Danishefsky Samuel J. Synthesis of epothilones, intermediates thereto and analogues thereof
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US7649006B2 (en) 2002-08-23 2010-01-19 Sloan-Kettering Institute For Cancer Research Synthesis of epothilones, intermediates thereto and analogues thereof
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US20090149516A1 (en) * 2002-08-23 2009-06-11 Danishefsky Samuel J Synthesis of Epothilones, Intermediates Thereto, Analogues and Uses Thereof
US20050282927A1 (en) * 2004-06-17 2005-12-22 Zhang-Lin Zhou Latex particulates with active ester functional groups
US7384990B2 (en) * 2004-06-17 2008-06-10 Hewlett-Packard Development Company, L.P. Latex particulates with active ester functional groups
US8685668B2 (en) 2005-02-11 2014-04-01 University Of Southern California Method of expressing proteins with disulfide bridges
US20080064634A1 (en) * 2006-05-01 2008-03-13 Markland Francis S Jr Combination therapy for treatment of cancer
US8008256B2 (en) 2006-05-01 2011-08-30 University Of Southern California Combination therapy for treatment of cancer
WO2009132253A1 (fr) 2008-04-24 2009-10-29 Bristol-Myers Squibb Company Utilisation de l'épothilone d dans le traitement des maladies associées à la protéine tau, y compris la maladie d'alzheimer
US8802394B2 (en) 2008-11-13 2014-08-12 Radu O. Minea Method of expressing proteins with disulfide bridges with enhanced yields and activity

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